Synthesis of 5-substituted 2'-deoxyuridines

Abstract

A series of thymidylate synthetase inhibitors was synthesized, some of which were potential irreversible inhibitors. 5-Formyl-2'-deoxyuridine (9) and its dithiolane derivative 11 were prepared by condensation of the bis(trimethylsilyl) derivative of 5-formyluracil dimethyl acetal and the protected chloro sugar followed by saponification of the protective groups. 5-Acetyl-2'-deoxyuridine (15) was prepared in the same way from 5-acetyluracil. Treatment of the diester of 5-allyl-2'-deoxyuridine (17 or 22) with m-chloroperbenzoic acid gave the corresponding epoxide. Dimethylamine removed the ester groups and opened the epoxide to give the amino alcohol 24. The diester of 5-chloromethyl-2'-deoxyuridine (27) treated with methanol or sodium azide gave 5-methoxymethyl- (29) and 5-azidomethyl- (31) 2'-deoxyuridines. Compound 27 also was converted to 5-iodoacetamidomethyl-2'-deoxyuridine by treatment with ammonia, chloroacetyl chloride, base saponification, and finally sodium iodide.

Thymidylate synthetase-deficient mouse FM3A mammary carcinoma cell line as a tool for studying the thymidine salvage pathway and the incorporation of thymidine analogues into host cell DNA

“…The test compounds and their sources were as follows: dThd (Sigma), dUrd (Sigma), 5-fluoro-dUrd (Aldrich), 5-chloro-dUrd (Calbiochem-Behring), 5-bromo-dUrd (Sigma), 5-iodo-dUrd (Sigma), 5-trifluoromethyl-dUrd (P-L Biochemicals), 5-hydroxymethyl-dUrd (Calbiochem-Behring), 5-azidomethyl-dUrd (Kampf et al, 1976;De Clercq et al, 1979b), 5-formyl-dUrd (Park et al, 1980), 5-cyano-dUrd (Torrence et al, 1977), 5ethynyl-dUrd (Barr et al, 1978;De Clercq et al, 1979a), 5-vinyl-dUrd (De Clercq et al, 1979a, (E)-5-(2-chlorovinyl)-dUrd (De Clercq et al, 1979a), (E)-5-(2-bromovinyl)-dUrd (De Clercq et al, 1979a;Jones et al, 1979), (E)-5-(2-iodovinyl)-dUrd (De Clercq et al, 1979a), 5-ethyl-dUrd (Swierkowski & Shugar, 1969;De Clercq & Shugar, 1975), 5-propyl-dUrd (De Clercq et al, 1978), 5methylthiomethyl-dUrd (De Clercq et al, 1979bSchmidt et al, 1980), 5-methylsulphinylmethyl-dUrd (Schmidt et al, 1980), 5-(1,3-dithiolan-2-yl)-dUrd (Park et al, 1980), 5-thiocyano-dUrd (De Clercq et al, 1975, 5-nitro-dUrd (provided by M. Robins, Edmonton, Alberta, Canada), 5-hydroxy-dUrd (Sefochem Fine Chemicals, Emek Hayarden, Israel), 5-propynyloxy-dUrd (Torrence et al, 1978).…”

Synthesis of 5‐Formyl‐2′‐Deoxyuridine and Its Incorporation into Oligodeoxynucleotides

“…dfU has been synthesized by several different methods, including classical condensation using 5‐formyluracil dimethyl acetal (Kampf et al, ), oxidation of a 5‐hydroxymethyl group using pyridinium dichromate (Whale et al, ), oxidation of the thymidine using bromine under photolysis (Bärwolff and Langen, ), and a Pd‐catalyzed cross‐coupling reaction using CO (Crouch and Eaton, ). In this unit, oxidation of the 5‐methyl group of thymidine derivatives is accomplished using K 2 S 2 O 8 , CuSO 4 ·5H 2 O, and 2,6‐lutidine in aqueous CH 3 CN using a slight modification of the original method (Itahara et al, ; Matsuda et al, ).…”

Toward Orthopoxvirus Countermeasures: A Novel Heteromorphic Nucleoside of Unusual Structure

“…[26][27][28] Benzofuran congeners form the nucleus of many biological active molecules. [29][30][31][32] Singh et al 33 gained entry to these fused pyrans by reactions of 1,3-oxazinanes and oxazolidines with various carbon nucleophiles.…”

“…We adapted this to the reaction of 5-formyl-2′-deoxyuridine with malononitrile and 1,3-cyclohexanedione to obtain a novel nucleoside. The synthesis was carried out using 5-formyl-2′-deoxyuridine [26][27][28] in a multicomponent reaction with malononitrile and 1,3-cyclohexanedione in EtOH to give 5-(2-amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-1-(2-deoxypentofuranosyl)pyrimidine-2,4(1H,3H)-dione (2) (Scheme 1). Compound 2 was obtained as a 1:1 diastereomeric mixture arising from the generation of a chiral carbon at position 4 of the chromone ring.…”